Context Memantine is a low- to moderate-affinity, uncompetitive N-methyl-D-aspartate receptor antagonist. Controlled
trials have demonstrated the safety and efficacy of memantine monotherapy
for patients with moderate to severe Alzheimer disease (AD) but no controlled
trials of memantine in patients receiving a cholinesterase inhibitor have
been performed.
Objective To compare the efficacy and safety of memantine vs placebo in patients
with moderate to severe AD already receiving stable treatment with donepezil.
Design, Setting, and Participants A randomized, double-blind, placebo-controlled clinical trial of 404
patients with moderate to severe AD and Mini-Mental State Examination scores
of 5 to 14, who received stable doses of donepezil, conducted at 37 US sites
between June 11, 2001, and June 3, 2002. A total of 322 patients (80%) completed
the trial.
Interventions Participants were randomized to receive memantine (starting dose 5 mg/d,
increased to 20 mg/d, n = 203) or placebo (n = 201) for 24 weeks.
Main Outcome Measures Change from baseline on the Severe Impairment Battery (SIB), a measure
of cognition, and on a modified 19-item AD Cooperative Study–Activities
of Daily Living Inventory (ADCS-ADL19). Secondary outcomes included
a Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus),
the Neuropsychiatric Inventory, and the Behavioral Rating Scale for Geriatric
Patients (BGP Care Dependency Subscale).
Results The change in total mean (SE) scores favored memantine vs placebo treatment
for SIB (possible score range, 0-100), 0.9 (0.67) vs –2.5 (0.69), respectively
(P<.001); ADCS-ADL19 (possible score
range, 0-54), –2.0 (0.50) vs –3.4 (0.51), respectively (P = .03); and the CIBIC-Plus (possible score range, 1-7),
4.41 (0.074) vs 4.66 (0.075), respectively (P = .03).
All other secondary measures showed significant benefits of memantine treatment.
Treatment discontinuations because of adverse events for memantine vs placebo
were 15 (7.4%) vs 25 (12.4%), respectively.
Conclusions In patients with moderate to severe AD receiving stable doses of donepezil,
memantine resulted in significantly better outcomes than placebo on measures
of cognition, activities of daily living, global outcome, and behavior and
was well tolerated. These results, together with previous studies, suggest
that memantine represents a new approach for the treatment of patients with
moderate to severe AD.
Alzheimer disease (AD) is a neurodegenerative disorder characterized
by cognitive decline, impaired performance of activities of daily living,
and behavioral and psychiatric signs and symptoms. Pathological features of
AD include intraneuronal neurofibrillary tangles containing abnormally phosphorylated
tau protein, extracellular amyloid plaques containing the peptide β amyloid,
neuronal cell death, and anatomic as well as functional impairment of neurotransmitter
systems.1,2 Alzheimer disease
affects approximately 4.5 million people in the United States.3 Treatments
approved by the Food and Drug Administration were previously limited to monotherapy
with cholinesterase inhibitors in patients with mild to moderate AD.2 In October 2003, the Food and Drug Administration
approved memantine for the treatment of moderate to severe AD; memantine is
now available in more than 40 countries worldwide.
Memantine, a low- to moderate-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, represents
the first member of a new class of medications showing clinical benefit and
good tolerability in AD. Although other NMDA receptor modulators (eg, milacemide
and D-cycloserine) have failed in development as potential
AD therapeutic agents,4,5 memantine
has exhibited efficacy and safety in a recent placebo-controlled trial in
outpatients with moderate to severe AD and in an earlier study in nursing
home patients with dementia.6,7 An
open-label study suggested that the combination of memantine and various cholinesterase
inhibitors was well tolerated.8 We hypothesized
that administration of memantine to patients with moderate to severe AD receiving
stable donepezil therapy would result in clinical benefit and would be safe
and well tolerated.
The trial was conducted from June 11, 2001, through June 3, 2002. Participants
were recruited from 37 US sites; 404 patients who had a diagnosis of probable
AD, according to the National Institute of Neurological and Communicative
Disorders and Stroke–Alzheimer Disease and Related Disorders Association
criteria, were enrolled. Inclusion criteria were as follows: Mini-Mental State
Examination (MMSE) score of 5 to 14 at both screening and baseline; minimum
age of 50 years; a recent magnetic resonance imaging or computed tomographic
scan (within 12 months) consistent with a diagnosis of probable AD; ongoing
cholinesterase inhibitor therapy with donepezil for more than 6 months before
entrance into the trial and at a stable dose (5-10 mg/d) for at least 3 months;
a knowledgeable and reliable caregiver to accompany the patient to research
visits and oversee the administration of the investigational agent during
the trial; residence in the community; ambulatory or ambulatory-aided (ie,
walker or cane) ability; and stable medical condition. Patients were permitted
to continue receiving stable doses of concomitant medications, including antidepressants,
antihypertensives, anti-inflammatory drugs, atypical antipsychotics, antiparkinsonian
drugs, anticoagulants, laxatives, diuretics, and sedatives/hypnotics.
Patients were excluded for clinically significant B12or folate
deficiency; active pulmonary, gastrointestinal, renal, hepatic, endocrine,
or cardiovascular disease; other psychiatric or central nervous system disorders;
computed tomographic or magnetic resonance imaging evidence of clinically
significant central nervous system disorders other than probable AD; dementia
complicated by other organic disease; or a modified Hachinski Ischemia Score9 of more than 4 at screening. Written informed consent
was obtained from the caregiver and either the patient (if possible) or a
legally acceptable representative (if different from the caregiver) before
the initiation of any study-specific procedures. The study was reviewed and
approved by the institutional review board at each site.
This study was a prospective randomized, placebo-controlled, parallel-group,
fixed-dose trial in which participants were assigned to double-blind treatment
for 24 weeks, with a 1- to 2-week single-blind placebo lead-in period before
randomization solely to assess compliance. Patients were randomly allocated
to 1 of the 2 treatment groups in permuted blocks of 4 in accordance with
the randomization list generated and retained by the Department of Biostatistics
at Forest Laboratories. At the baseline visit, each investigator sequentially
assigned a randomization number to each patient. No individual patient randomization
code was revealed during the trial.
Patients assigned to double-blind memantine treatment were titrated
in 5-mg weekly increments from a starting dose of 5 mg/d to 20 mg/d (administered
as two 5-mg tablets twice daily) at the beginning of week 4. Masked study
medication was supplied to each study site for dispensation in blister packs
at each visit. Drug and placebo tablets were visually identical and all patients
received 4 tablets of study medication daily (in combinations of memantine
[5 mg] and matching placebo tablets). All patients were to maintain stable
donepezil therapy at entry dose as prescribed by the patient's physician for
the duration of the study; adherence to this protocol was monitored by routine
assessment of concomitant medication use. Any change in the dosing regimen
or discontinuation of donepezil was recorded, and patients were discontinued
from the study if the inclusion criterion of concomitant donepezil therapy
was no longer met. From week 3 to the end of week 8 of double-blind treatment,
transient dosage adjustments for memantine treatment were permitted for patients
experiencing dose-limiting adverse events. All patients receiving memantine
were required to receive the target dose of 20 mg/d by the end of week 8.
Patients not tolerating the target dose by week 8 were disenrolled. Adherence
with study medication was assessed by returned tablets and more than 95% of
both treatment groups had more than 75% compliance (95% for the placebo-treatment
group and 96.5% for the memantine-treatment group). Most patients who completed
the double-blind phase entered the currently ongoing open-label extension.
Cognitive, functional, and global outcome measures were obtained at
baseline and at the end of weeks 4, 8, 12, 18, and 24, unless otherwise specified.
Patients who discontinued prematurely were evaluated during the final visit.
The primary efficacy parameters were the change from baseline on the Severe
Impairment Battery (SIB) and on a modified 19-item AD Cooperative Study–Activities
of Daily Living Inventory (ADCS-ADL19) at week 24.
The SIB is a 40-item test developed for the evaluation of cognitive
dysfunction in patients with more severe AD. Six primary subscales assess
memory, orientation, language, attention, visuospatial ability, and construction.
In addition, the scale assesses praxis, social interaction, and orienting
to name.10,11 Validity, reliability,
and sensitivity to longitudinal change have been established.10,11 The
SIB scores range from 0 to 100, with higher scores reflecting higher levels
of cognitive ability. The SIB was assessed at baseline and all subsequent
visits.
The ADCS-ADL19 was the second primary efficacy instrument.12 This 19-item subset of the original 42-item inventory
focuses on items appropriate for the assessment of later stages of dementia
(ie, the level of independence in performing everyday tasks including eating,
walking, grooming, telephone use, hobbies, complex tasks, and communications).
The sensitivity and reliability of this modification have been established.13 The ADCS-ADL19 was administered as an
interview to the patient's caregiver and focused on the performance of each
activity of daily living during the previous 4 weeks. Possible scores range
from 0 to 54. Higher scores reflect higher levels of functioning. The ADCS-ADL19 was assessed at baseline and all subsequent visits.
The secondary outcomes included a Clinician's Interview-Based Impression
of Change Plus Caregiver Input (CIBIC-Plus),14 the
Neuropsychiatric Inventory (NPI), and the Behavioral Rating Scale for Geriatric
Patients (BGP). The CIBIC-Plus was administered according to the format of
the Alzheimer Disease Cooperative Study–Clinician's Global Impression
of Change. The CIBIC-Plus is used to assess the effect of medication on overall
clinical status in patients with dementia, incorporating caregiver observations
as well as patient interviews. Change is rated on a scale from 1 (marked improvement)
to 7 (marked worsening). A global assessment of severity of illness was made
at baseline; the CIBIC-Plus was assessed at all postbaseline visits.
The NPI was designed to assess the frequency and severity of behavioral
symptoms in patients with dementia, based on an interview of the caregiver.15 The 12-item version of the instrument was used with
a total score ranging from 0 to 144. Higher scores reflect greater symptoms.
The NPI was assessed at baseline, at the end of week 12, and at the final
visit.
The BGP consists of 35 items (scored 0, 1, or 2 by the rater) assessing
observable aspects of cognition, function, and behavior.16 A
higher score reflects worse function. The BGP care dependency subscale reflects
cognitive and functional characteristics associated with increased need for
care. The BGP was administered at baseline and the final visit.
The Functional Assessment Staging (FAST) was administered as an index
of staging and not as a secondary outcome.17 The
FAST evaluates a patient's ability to perform daily and necessary life activities
and is divided into 7 major stages, from normality (FAST stage 1) to severe
dementia (FAST stage 7). Stages 6 and 7 are further divided into 11 substages
(6a to 6e and 7a to 7f), each of which is based on specific functional deficits.
The FAST was administered at baseline and the final visit.
Concomitant medications and vital signs were recorded at every visit;
adverse events were recorded at baseline and all subsequent visits; and laboratory
tests, electrocardiograms, and physical examinations were performed at the
screening and final visits.
Assuming a hypothetical effect size of 0.35, a sample size of at least
170 patients in each treatment group provided a 90% power at a 2-sided α
level of .05, based on a 2-sample t test for change
from baseline to week 24 in both SIB and ADCS-ADL19 scores.
Three populations were considered in the statistical analyses. The randomized
population consisted of all patients randomized into the study (n = 404);
the safety population consisted of all randomized patients who received at
least 1 dose of double-blind study medication (n = 403); the modified intent-to-treat
population specified by the protocol consisted of patients in the safety population
who completed at least 1 postbaseline SIB or ADCS-ADL19 assessment
(n = 395). The statistical analysis plan for this study stipulated that only
postbaseline data could be carried forward. Particularly for the CIBIC-Plus,
it is not possible to carry forward baseline data because by definition this
is a change score and is not applicable to baseline. All efficacy analyses
were based on the modified intent-to-treat population. Primary efficacy analyses
were conducted by using the last observation carried forward (LOCF) approach
for missing data imputation. Supportive analyses were performed by using the
observed case approach. Change from baseline was compared between memantine
and placebo groups using a 2-way analysis of covariance, with treatment group
and center as main effects and baseline total score as the covariate. The
study was to be declared positive if memantine was statistically significantly
better than placebo (P<.05) on both the SIB and
ADCS-ADL19. For categorical measures, the Cochran-Mantel-Haenszel
statistic using modified Ridit scores (Van Elteren test) controlling for study
center was used to compare distributions between memantine and placebo groups.
No interim analyses were performed. SAS version 6.12 (SAS Institute, Cary,
NC) was used for all analyses.
The trial profile is summarized in Figure 1. Of the 404 patients who entered the study, 201 were randomized
to placebo and 203 were randomized to memantine (1 in the memantine group
withdrew consent before receiving treatment). No patients were excluded during
the placebo lead-in period for lack of compliance. Significantly more participants
in the memantine group (n = 172, 85.1%) completed the study than in the placebo
group (n = 150, 74.6%, P = .01). No patients discontinued
because of changes in administration of donepezil.
The demographic and clinical characteristics of the 2 groups at baseline
are summarized in Table 1. Patients
in the memantine group were slightly heavier (P =
.003) than those in the placebo group; retrospectively adding this variable
to the analysis of covariance did not affect the primary outcomes. No clinically
relevant group differences were observed for the duration of donepezil use
before baseline or for any other characteristic at baseline. Most patients
(87%) had a FAST rating between 4 and 6c. The most frequent medical conditions
were not recorded, but the following body systems were noted to be affected
at screening for placebo and memantine groups, respectively: eyes-ears-nose-throat
(43% and 43%), neurological (34% and 38%), appearance/skin (40% and 33%),
musculoskeletal (29% and 29%), cardiovascular (20% and 23%), abdomen (12%
and 17%), head/neck (6% and 9%), other (10% and 9%), and pulmonary (3% and
5%). The most frequent medication classes (>20%) used during treatment with
placebo and memantine, respectively, were vitamins (74% and 77%), analgesics
(48% and 48%), antidepressants (36% and 36%), mineral supplements (22% and
27%), lipid-reducing agents (23% and 25%), anxiolytics/neuroleptics (26% and
22%), and anti-inflammatory agents (21% and 24%). There were no statistically
significant differences between groups in the number or type of medical disorders
experienced previously or at the time of enrollment, or in the number or type
of concomitant medications used during the study.
Statistically significant benefits of treatment with memantine vs treatment
with placebo were observed on all primary and secondary outcome measures as
presented. Table 2 summarizes
primary and secondary efficacy outcomes at week 24 and at end point, using
both the observed case and LOCF analytical approaches.
Analyses using the LOCF approach showed a statistically significant
benefit of memantine treatment vs treatment with placebo on the SIB (P<.001) and the ADCS-ADL19 (P = .03), as did analyses using the observed case approach (P<.001 for SIB; P = .02 for ADCS-ADL19). Post hoc analyses including all randomized patients also showed
statistically significant benefits consistent with analyses using the modified
intent-to-treat population (for SIB, P<.001 and
for ADCS-ADL19, P = .03).
Figure 2 depicts the mean
change from baseline by visit and at end point on the SIB by using observed
case and LOCF, showing statistically significant differences between the memantine
and placebo groups at all visits beginning at week 8; the mean SIB values
for the patients receiving memantine remained above baseline throughout the
trial. Figure 2 also depicts the
mean change in total ADCS-ADL19 from baseline by visit and at end
point by using observed case and LOCF, respectively, showing a statistically
significant difference (P<.05) from placebo beginning
at week 4.
A CIBIC-Plus score was used as a measure of overall clinical response
to therapy. The mean CIBIC-Plus score was statistically significantly better
for the memantine group vs the placebo group using both observed case and
LOCF (Table 2). Furthermore, 55%
of the memantine group was rated as improved or unchanged vs 45% of the placebo
group at end point. Figure 3 provides
the distribution of CIBIC-Plus ratings at end point using LOCF analysis.
The total NPI score was significantly lower for the memantine group
compared with the placebo group at week 24 (P = .01
with observed case analysis and P = .002 with LOCF),
representing fewer behavioral disturbances and psychiatric symptoms for patients
in the memantine group. The BGP care dependency subscale was also statistically
significantly improved for the memantine group compared with the placebo group
(P = .001 using observed case and P = .001 using LOCF; Table 2).
Overall treatment-emergent adverse events are summarized in Table 3. More participants (n = 25, 12.4%)
in the placebo-treated group discontinued prematurely because of adverse events
than in the memantine group (n = 15, 7.4%; Figure 1). The adverse event most often associated with discontinuation
was confusion, resulting in discontinuation in 1.5% of patients in the placebo
group and 2% in the memantine group.
Adverse events occurred in 72% of the placebo and 78% of the memantine
groups. Most adverse events were rated as mild or moderate in severity and
were judged to be not related to study drug for participants in both treatment
groups. The only adverse events that occurred in at least 5% of the memantine
group and with an incidence of at least twice that of the placebo group were
confusion (7.9% vs 2.0%, respectively; P = .01) and
headache (6.4% vs 2.5%, respectively; P = .09). By
similar criteria, lower incidences of diarrhea (4.5% vs 8.5%) and fecal incontinence
(2.0% vs 5.0%) were observed in the memantine group compared with the placebo
group, respectively. Other gastrointestinal effects of interest for patients
receiving cholinesterase inhibitors included nausea, which was reported by
3.5% of the placebo group and 0.5% of the memantine group, and constipation,
which was reported by 1.5% of the placebo group and 3.0% of the memantine
group.
Of the patients who experienced confusion, 4 (25%) of 16 patients receiving
memantine discontinued treatment because of this adverse event, whereas 3
(75%) of 4 patients receiving placebo did so. In most of the patients receiving
memantine, confusion was rated as mild, occurred at a median of 32 days, and
remitted within 2 weeks. In patients receiving placebo, confusion was more
likely to be rated as severe, occurred at a median of 55 days, and did not
remit. No patients discontinued because of headache, which usually lasted
1 day.
No clinically significant differences were detected between treatment
groups in the mean change from baseline to end point or in the incidence of
potentially clinically significant values for laboratory tests, vital sign
measurements, or electrocardiogram parameters.
To our knowledge, this is the first published, prospective, double-blind,
placebo-controlled study examining the benefits of an NMDA receptor antagonist
in patients with AD receiving a stable dose of donepezil. Efficacy of memantine
was significantly better than placebo for treatment of moderate to severe
AD in community-dwelling patients. Specifically, measures of cognitive function,
activities of daily living, behavior, and clinical global status were significantly
improved with memantine compared with placebo. Treatment with memantine during
the 6-month trial in patients with MMSE scores of 5 to 14 resulted in the
maintenance of cognitive function (0.9 increase in SIB score compared with
baseline), whereas treatment with placebo was associated with cognitive decline
(2.5 decrease in SIB score compared with baseline). In comparison, the AD
Cooperative Study group reported that for untreated patients with AD with
MMSE scores of 5 to 9, the mean deterioration rate on the SIB was roughly
3.19 per month and for untreated patients with AD with MMSE scores of 10 to
15, the rate of change was 2.08 per month.10 Treatment
with memantine was associated with less decline on the CIBIC-Plus.
These efficacy findings confirm and extend results from previous placebo-controlled
trials of memantine in dementia. A 12-week multicenter European trial6 of memantine 10 mg/d was conducted in 166 nursing
home residents with severe dementia, including both Alzheimer type and vascular
dementias, diagnosed by Diagnostic and Statistical Manual
of Mental Disorders, Revised Third Edition criteria18 (mean
baseline MMSE of 6.3). Significant benefit of memantine vs placebo was observed
on the Clinician's Global Impression of Change and the BGP care dependency
subscale, and there were no clinically relevant differences in adverse events
between memantine (21%) and placebo (22%) groups. A more recent 28-week multicenter
US trial of memantine 20 mg/d monotherapy was conducted in 252 patients with
moderate to severe probable AD by the National Institute of Neurological and
Communicative Disorders and Stroke– Alzheimer Disease and Related Disorders
Association criteria and who were not permitted to receive a cholinesterase
inhibitor.7 Significant benefit of memantine
treatment was observed on the ADCS-ADL19, an assessment of function,
and on the SIB, an assessment of cognition using both observed case and LOCF
approaches, and on the CIBIC-Plus in the observed case but not the LOCF analysis.
Adverse events were similar between the memantine (84%) and placebo (87%)
groups.
Patients in the memantine monotherapy outpatient study7 were
more cognitively impaired (mean baseline MMSE of 7.9), more functionally impaired
(mean baseline ADCS-ADL19 score of approximately 27), and experienced
more psychopathology (mean baseline NPI of approximately 20; rates of agitation
as an adverse event in 32% and 18% of patients treated with placebo and memantine,
respectively) than patients included in this trial. In addition, the magnitude
of the memantine-placebo differences in outcomes common to both studies, as
well as the magnitude of decline in most measures over time, was greater in
the memantine monotherapy study than observed in this trial. This finding
may be related to the higher severity of dementia in patients enrolled in
the memantine monotherapy trial or because the present trial required donepezil
therapy and permitted use of most psychotropics, factors which may have contributed
to slower rates of decline in both the memantine and placebo groups. However,
this type of inference is speculative given the absence of patients who were
not treated with donepezil. Similar to the finding in the present trial, discontinuation
rates because of adverse events in the monotherapy study were lower in patients
receiving memantine than in those receiving placebo (10% vs 17%, respectively).7 These trials support the efficacy of memantine for
patients with moderate to severe AD.
Memantine administered at a dosage of 20 mg/d to patients receiving
stable doses of donepezil was safe and well tolerated. Significantly more
patients receiving placebo discontinued the trial than patients receiving
memantine and the rate of discontinuation because of adverse events was lower
in the memantine-treated group than in the placebo-treated group. The incidence
of individual adverse events was generally similar in the 2 groups. Confusion,
although occurring at a low frequency, was more common in patients receiving
memantine than in those patients receiving placebo. However, it did not lead
to a greater proportion of discontinuations and was mild in intensity and
duration. The gastrointestinal adverse effects associated with cholinergic
compounds were more commonly reported by patients receiving placebo, which
was suggestive of a possible amelioration of these adverse events by the addition
of memantine treatment to patients receiving a stable regimen of donepezil
therapy. There were no clinically significant memantine-related mean changes
in laboratory test results, vital signs, or electrocardiogram parameters.
There are limitations to the generalizability of our results. The trial
did not address different doses or titration rates, the use of other cholinesterase
inhibitors besides donepezil, or the impact of commencing memantine therapy
before donepezil. Although there is no a priori reason to expect different
results with other cholinesterase inhibitors, studies of memantine in combination
with other cholinesterase inhibitors are being conducted to address this issue.
Furthermore, results from an open-label European trial indicated that tolerability
was not affected when donepezil or other cholinesterase inhibitors were administered
to patients already receiving memantine or vice versa.8 Preclinical
studies show that memantine does not affect the inhibition of acetylcholinesterase
by donepezil, nor does it bind to muscarinic receptors.19-21 Furthermore,
in healthy volunteers, no pharmacokinetic or pharmacodynamic interactions
were observed between memantine and donepezil.22 Although
memantine has demonstrated positive cognitive effects in patients with mild
to moderate vascular dementia, the efficacy of memantine administered alone
or along with any cholinesterase inhibitor in other forms of dementia was
not systematically evaluated in this trial.23,24
The long-term effects of memantine and cholinesterase inhibitor treatment
were not addressed in this double-blind trial but are the focus of the open-label
extension and other ongoing trials. Considering that patients in this study
had been receiving stable long-term donepezil therapy before enrollment, it
is possible that participants were more likely to experience good tolerability
and efficacy in the trial, perhaps because of having fewer medical problems
or experiencing a slower rate of decline than patients without any prior AD
treatment. However, the use of concomitant medications was typical for this
elderly patient population and was similar between the groups. In addition,
the dropout rate was approximately 15% in the memantine group vs approximately
25% in the placebo group, a phenomenon that perhaps led to an underestimation
of the effect of memantine.
Drugs that target the glutamatergic system appear to have a therapeutic
role in AD.25,26 Memantine may
block pathological activation of NMDA receptors while dissociating from the
NMDA receptor channel during normal physiological conditions,20 in
theory improving cognition in states of glutamatergic excess. It is plausible
that combining donepezil and memantine, which affect separate neurotransmitter
systems, may confer independent clinical benefits. However, given the complex
interconnection of different neurotransmitter systems, a synergistic mechanism
is also plausible. Although the specific mechanisms and interactions between
these therapies have not yet been defined, this and other studies demonstrate
that memantine alone or together with a cholinesterase inhibitor results in
significantly better outcomes than placebo in patients with moderate to severe
AD.
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